1-halomercuri, trihalo benzimidazoles



United States Patent l-HALOlVlERCURI, TRIHALO BENZIMIDAZOLES Karl A.Folkers, Plainfield, and 'Clitford H. Shunk, Westfield, N; J., assignorsto Merck &.Co.,'lnc., Rahway, N. J., a corporation of New Jersey NoDrawing. Original application November 23', 1956,

Serial No. 623,766. Divided and this application August 26, 1957, SerialNo. 680,418

i Q 8'Claims. (Cl. 260-299) v This application is a continuation in-partof our copending application Serial No. 422,662, filed April 12,

1954, now abandoned, and a divisionof our copending application, SerialNo. 623,766, filed November 23,

This invention relates to the preparation of the new chemical compounds,4,5,6-(5,6,7)-trihalo-l-D-ribofuranosylbenzimidazole, to acid salts, andto water soluble estersthereof. It is also concerned with preparation ofthe novel chemical compounds produced as intermediates in the synthesisof 4,5,6-(5,6,7) trihalo-1-D- ribofuranosylbenzimidazole.

Certain compounds of this invention possess marked and elfectiveanti-viral activity against influenza B virus. For example,4,5,6-(5,6,7) trichloro-l D-ribofuranosylbenzimidazole' has sevenhundred to eight hundred times the inhibitory action of benzirnidazoleagainst influenza B virus when tested in accordance with the methodlater described A number of substitutedbenzimidazoles out side the scopeof this invention have also'been tested for activity against influenza Bvirus and have been found to have little inhibitory activity. p

The compositions of this invention are prepared by reducingl,2,3-trihalo-4,S-dinitrobenzene'to form1,2,3-trihalo-4,5-diaminobenzene. having the following formula:

2,876,230 P wtai ea 31. .9.5?

wherein X represents a. chlorine or bromine atom and R represents anacyl radical. The new compound formed in this reaction is4,5,6-(5,6,7)-trihalo-1-(triacyl- D-ribofuranosyl)-benzimidazole, andhas the formula wherein X represents a halogen atom; The halogen atomsmay be the same or difierent.

The 1,2,3-trihalo-4,5-diaminobenzene thus formed is then reacted withformic acid and a mineral acid to form 4,5,6-nihalo-benzimidazole havingthe following formula:

X: wherein X represents a halogen atom, which is in turn treated with amercuric halide to produce the newl-halomercuri-4,5,6-(5,6,7)-trihalobenzimidazole, having the followingformula:

The 4,5,6 (5,6,7) trihalo 1 D ribofuranosyl benzimidazole acid salts areprepared by reacting 4,5,6-(5,6,7)-trihalo-1-D-ribofuranosylbenzimidazole, with. an acid in aqueousor alcoholic solution. The salt maybe isolated by removal of solventunder reduced pressure. Acid salts, such as the4,5,6-(5,6,7)-trihalo-l-D-ribo= furanosylbenzimidazole hydrochloride,4,5,6-(5,6,7)-trihalo l D ribofuranosylbenzimidazole hydrobromide, 4,5,6(5,6,7) trihalo 1 D ribofuranosylben- -z imidazole sulfate, 4,5,6(5,6,7) trihalo 1 D ribofuranosylbenzimidazole citrate and4,5,6-(5,6,7.)'-trihalo- 1 D-ribofuranosylbenzimidazole acetate, may beprepared in this manner.

In addition to the acid salts, water soluble esters such as thephosphate and tricarballylate of these novel 4,5,6- (5,6,7) trihalo l Dribofuranosylbenzimidazoles may be prepared by reacting the parentcompound with a suitable esterifying agent. Pyrophosphoric acid or phosphorous oxychloride pretreated with one molar equivalent of water aresuitable phosphorolating agents. It is believed that the phosphate esterforms primarily at the 5 position although 2 and 3 esters may also bepresent.

1,2,3-trichloro-4,S-dinitrobenzene, one of the starting materials inthis invention, may be prepared as described by .Hufier, Rec. Trav.Chim. 40, 451.

The 1-halo-2,3,S-triacyl-D-ribofuranose employed as an intermediate inthis process may be prepared by reacting tetraacyl-D-ribofuranose with ahalogen halide.

In accordance with the process of this invention 1,2,3-trichloro-4,5-dinitrobenzene is suspended in concentrated hydrochloricacid. Mossyv tin is added to the suspension and1,2,3-trichloro-4,S-diaminobenzene produced by heating at from 50l00C.for from 15 minutes to 2 hours.

The l,2,3-trichloro-4,S-diaminobenzene is reacted with formic acid andhydrochloric acid to form 4,5 ,6-trichlorobenzimidazole.-' The free baseis recovered by neutralization of the mineral acid with a base andcrystallization.

The 4,5,6-trichlorobenzimidazole is next reacted with mercuric chloridein an inert solvent in the presence of an alkali metal base or alkalineearth metal base to form 1-chloromercuri-4,5, 6-trichlorobenzimidazole.It has been found that the time'and temperature of the reaction are notcritical, although elevated temperatures accelerate the reaction. Anyinert liquid medium in which the reactants are soluble but the reactionproduct is insoluble may be utilized as a medium in the reaction of4,5,6-trichlorobenzimidazole and mercuric chloride. Water or loweralkanols, for example, ethanol, propanohbutanol and amyl alcohol, may beused. Suitablealkali metal bases or'alkaline earth metal bases which maybe employed in the process include sodium hydroxide, potassiumhydroxide, calcium hydroxide, sodium carbonate, potassium bicarbonate,and the like. It is preferred touse about onev equivalent of base tobind the free acid liberated in the reaction.

The 1-chloromercuri-4,5,6-(5,6,7)-trichlorobenzimidazole is .thenreacted with 1-halo-2,3,S-triacyl-D-ribofw ranose in the presence of asolvent, and 4,5,6-(5,6,7)- trichloro 1 (triacyl D ribofuranosyl)benzimidazole recovered. Compounds such as 1-chloro-2,3,5-triacetyl-D-ribofuranose, l-bromo-2,3,S-triacetyl-D-ribofuranosej 1-chloro 2,3,5 'tripropionyl D ribofuranose, 1-'chloro-2,3,5-tributyry1-Dribofuranose, l-bromo- 2,3,S-tribenzoyl-D-ribofuranose or1-chl0ro-2,3,5-tribenzoyl-D-ribofuranose may be employed. Examples ofsuitable solvents for the reaction are benzene, toluene and xylene.Xylene is the preferred solvent for the reaction since the refluxtemperature of xylene provides a convenient reaction temperature.

To produce the 4,5,6-(5,6,7)-trichloro-l-D-rib-ofuranosylbenzimidazole,the 4,5,6-(5,6,7)-trichloro-l-(triacyl- D ribofuranosyl) benzimidazoleis hydrolyzed. The hydrolysis may be carried out in either an alkalineor acid medium. In accordance with the preferred procedure, 4,5,6(5,6,7) trichloro 1 (triacyl D ribofuranosyl) -benzimidazole ishydrolyzed with methylalcohol in the presence of anhydrous ammonia.Anhydrous conditions are preferred for this reaction. Ammonia is alsopreferred since it is readily removed from the reaction mixture. Loweralkanols, such as methanol, ethanol, propanol and iso'propanol, may beemployed as solvents. If desired, acid hydrolysis may be conductedemploying aqueous alcoholic solutions containing a hydrohalic acid.

The 4,5,6 (5,6,7) trichloro 1 D ribofuranosylbenzimidazole acid .saltsare prepared by reacting 4,5,6-(S,6,7)-trichloro-1-D-ribofuranosylbenzimidazole with an acid in aqueousor alcoholic solution. The salt may be isolated by removal of solventunder reduced pressure.

4,5,6- (5,6,7) trichloro 1 D ribofuranosylbenzimidazole and closelyrelated compounds were tested for antiviral activity against influenza Bvirus as follows:

Groups of six chorioallantoic membranes, the membrane from anembryonated egg which serves as a source of living cells, were quarteredand each quarter placed in a separate tube containing 0.9 ml. of anutrient fluid comprising saline, glucose and salts. Each of these tubeswas inoculated with Lee influenza B virus diluted ten thousand times ina similar nutrient fluid, 0.1 ml. of the virus solution per tube. Toeach group of six inoculated tubes was added one of the compounds listedin Table I below. After thirty-six hours, hemagglutination titrationswere carried out on the individual samples using a 0.25% concentrationof chicken erythrocytes in solution. The geometric mean titer of eachgroup was then computed.

The concentration of each benzimidazole derivative necessary to give 75%inhibition of viral multiplication was determined. The comparativeactivity of benzimidazole derivatives is given below.

The number of the position of the substituents in each ofthe compoundsas given in the table is indicated in the following formula:

TABLE Inhibition rate S-methylbenzimidazole 1.95,6-dimethylbenzimidazole 1.9 2,5-dimethylbenzirnidazole 2.62-propyl-5-methylbenzimidazole 14.3 Z-ethyl-S-methylbenzimidazole 19.22,4,5,6,7-pentamethylbenzimidazole 16.3Z-isopropyl-S-methylbenzimidazole 20.6 5,6-dichloro-1-Dribopyranosylbenzimidazole 15.2

5,6 dichloro Z-methyl-l-D-ribofuranosylbenzimidazole 15.0

4,5,6 (5,6,7)-trichloro-1-D-ribofuranosylbenzimidazole 700-800 Thefollowing examples are given by way of illustration and not oflimitation.

Example 1 PREPARATION on 1,2,3-TRICHLORO-4,5-DIAMINO- BENZENE 01- No,o1- -NH,

I -O 01 N0, 01 NH:

Ten grams (0.037 mole) of 1,2,3-trichloro-4,5-dinitrobenzene wassuspended in 120 ml. of concentrated hydrochloric acid and heated on asteam bath. Mossy tin (15 g.) was added in small pieces with frequentshaking. Some concentrated hydrochloric acid was added from time to timeto rinse down the condenser. After all the tin was added, the mixturewas heated on a steam bath for one-half hour with frequent shaking. Thereaction mixture was diluted with about 1400 ml. of water and heateduntil solution was almost complete. To the mixture was added activatedcharcoal and the mixture filtered. The filtrate was cooled, whereupon acolorless precipitate formed. With cooling the mixture was made stronglyalkaline using 30% sodium hydroxide solution. The colorless precipitate,1,2,3-trichloro-4,5-diaminobenzene which formed was collected on afunnel and washed well with water. The precipitate was dissolved inabout 300 ml. of ether, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. There was obtained 6.0 g. of1,2,S-trichloro-4,5-diaminobenzene, M. P. -112" C.

In a similar manner other halogen atoms can be substituted for1,2,3-trichloro-4,5-dinitrobenzene as the starting material in the aboveprocedure. For example 1,2,3- tribromo-4,5-dinitrobenzene,l,2-dichloro-3-bromo-4,5-dinitrobenzene,1,2-dibromo-3-chloro-4,S-dinitrobenzene, 1,-3-dichloro-2-bromo-4,S-dinitrobenzene, 1,2,3-tri-iodo-4,5-dinitrobenzene, or 1,2-dichloro-3-iodo-4,5-dinitrobenzene may beemployed in this procedure to form the corresponding1,2,3-tribromo-4,S-diaminobenzene, 1,2-dichloro-3-bromo-4,5-diaminobenzene, 1,2-dibromo-3-chloro-4,5- diaminobenzene,l,3-dichloro-2-bromo-4,S-diaminobenzene,1,2,3-triiodo-4,S-diaminobenzene, and 1,2-dich1oro-3-iodo-4,5-diaminobenzene.

PREPARATION OF 4,5,6-TRICHLOROBENZIMIDAZOLE III NH: HCOOH 01 N\ on N112H01 01 N solid which appeared wascollected and washed with water. Driedin vacuo over potassium hydroxide, -it weighed 12.96 .g., M. P. 230,with softening at'200" C. It was then dissolved -on the steam bath in :amixture of 35 ml. 2.5 N hydrochloric acid and 500 m1. of water, treatedwith activated charcoal and filtered. This charcoaling procedure wasrepeated three times until the filtrate was colorless. The filtrate Wascooled and made just basic with 6 N ammonium hydroxide. The nearcolorless precipitate was refrigerated for three hours and was thencollected and washed with water. Dried in vacuo over potassium hydroxideit weighed 8.56 g., M. P. 215-217 C. (softening at 200 C.). This wasdissolved in 225 ml. of hot 50% ethanol, treated with activated charcoaland filtered by gravity with 2 x 15-m1. hot solvent mixture rinses,allowed to crystallize at room temperature and then placed in arefrigerator overnight. The nearly colorless crystals were collected andwashed with cold 50% ethanol. Dried in vacuo over potassium hydroxide,the nearly colorless 4,5,6-trichlorobenzimidazole weighed 6.95 g., M. P.226-228" C.

In a similar manner other halogen atoms can be substituted for1,2,3-trichloro-4,S-diaminobenzene as the starting material in the aboveprocedure. For example, 1,2,3-tribromo-4,S-diauiinobenzene, 'l,2dichloro-3-bromo- 4,5-diaminobenzene, l,2-dibromo-3-chloro-4,5 --diaminobenzene, 1,3-dichloro-2-bromo-4,5-diarninobenzene, 1,2,3-tri-iodo-4,5-diaminobeuzene or 1,2-dichloro-3-iodo-4,5-diaminobenzenemay be reacted with formic acid and a mineral acid to form thecorresponding 4,5,6-1tribromobenzimidazole,5,6-dichloro-4-bromo-benzimidazole, 5,6- dibromo-4-chlorobenzimidazole,4,6-dichloro-5-bromobenzimidazole, 4,5,6-triiodobenzimidazole, or5,6-dichloro-4- iodobenzimidazole.

1-CHLOROMERCURI-4,5,6-(5,6,7 -TRICHLOROBEN- ZIMIDAZOLE HgCl Five andfifty-three hundredths grams (0.025 mole) of4,5,6-trichlorobenzimidazole was dissolved in 250 ml. of hot 50%ethanol. To this mixture was added- 25 ml. of l N sodium hydroxide. Ahot solution of 6.88 g. (0.025 mole) of mercuric chloride in 50 ml. of50% ethanol was added with stirring. A gelatinous precipitate formedimmediately. The mixture was stirred and heated on the steam bath untilthe precipitate became grainy. It was, collected on a funnel and washedwith water. The cake was pressed as dry as possible on the funnel. Thel-ch1oromercuri-4,5,6-(5,6,7)-trichlorobenzimidazole dried in vacuo overpotassium hydroxide weighed 10.89 g.

In a similar manner other halogenated beuzimidazoles can be substitutedfor 4,5,6-trichlorobenzimidazole in the above procedure. For example,4,5,6-tribromobenzimidazole, 4,5-dichloro-6-bromobenzimidazole,4,5-dibromo- 6eclilorobenzimidazole, 4,6-dichlorod-bromobenzimidazole,4,5,6-triiodobenzimidazole and 4,5-dichloro-6-iodobenzimidazole may bereacted with .a mercuric halide to form the corresponding1-halomercuri-4,-5,6-(5,6,7)-tribromobenzimidazole,l-halomercuri-4,5-dichloro-6 bromo-(6,7-dichloro-5-bromo)-benzimidazole,l-halomercuri- 4,5-dibromo-6-chloro-(6,7-dibromo-5-dichloro)-benzimidazole, 1-halomercuri-4,6-dichloro-5-bromo- (5,7 dichloro-6-bromo)-;benzimidazole, l-halomercuri-4,5 ,6- 5 ,6,7) tri-iodobenzimidazole orl halomercuri-4,5-dichloro-6- iodo- 6,7-dichloro-5-iodo) -benzimidazole.

Mercuri bromide may be substituted for mercuric chloride to form thel-'bromomerouri-4,5,6-(5,6,7)-trihalobenzimidazole'iuthe above reaction.

1-chloro-2,3,S-triacetybD-ribofuranose was prepared by suspending 9.55grams (0.03 mole) of tetraacetyl-D -ribofuranose, M. P. 8-4'85 C. inabout 300 ml. of dry ether (dried over sodium) and saturated at 0 C.with anhydrous hydrogen chloride. The solution was protected frommoisture and stored in the cold room for three days. The solution wasthen evaporated in vacuo under anhydrous conditions at about 35 C. Thesyrup was reconcentrated three times adding about ml. of dry benzeneeach time. This was done to remove residual hydrogen chloride. The1-chloro-2,3,5-triacetyl-D-ribofuranose thus obtained was dissolved inabout 40 ml. of dry xylene and used at once in the following reaction.

Thirteen and sixty-eight hundredths grams (0.03 mole) of lchloromercuri-4,5,6-(5,6,7)-trichlorobenzimidazole was suspended in 1200ml. ofdry xylene in a 2-liter, 3- necked flask fitted with a stirrer, acondenser and a dropping funnel. About ml. of xylene was distilled toremove any moisture. The 1-chloro-2,3,5-triacetyl- D-ribofuranose inabout 40 m1. of dry xylene was added to the hot suspension in a steadystream. The mixture was refluxed gently with stirring for :four hours.It was cooled to room temperature and then refrigerated. The solidmaterial was collected, washed with xylene and pe troleum ether. About 3liters of petroleum ether was added to the filtrate. The precipitatethat separated was collected and washed with petroleum ether. Thecombined solids were extracted portionwise with about 700 ml. of warmchloroform. The combined chloroform solutionswere filtered and washedwith two ml. portions of 30% potassium iodide solution and twice withwater. The chloroform solution was dried over anhydrous magnesiumsulfate and concentrated under reduced pressure to leave 7.0 g. of alightly colored glass, crude 4,5,6-(5,6,

7) -trichloro-1-(triacetyl-D-ribofuranosyl) -benzimidazole.

In a manner similarly described in the above reaction, 1bromo-2,3,5-triacetyl-D-ribofurauose, '1-chloro-2, 3-,5- tripropionylD-ribofuranose, 1-chloroe2,3,5-tributyryl-D ribofuranose,l-bromo-2,3,5-tribenzoyl-D-ribofuranose or1-chloro-2,3,5-tribenzoyl-D-ribofuranose may be substituted for1-chloro-2,3,S-triacetyl-D-ribofuranose to form 4,5,6 (5,6,7)trihalo-l-.(triacyl-Dwribofuranosyl)-benzimidazoles, such as4,5,6-(5,6,7)-tribromo-1-(triacetyl-D- ribofuranosyl) benzimidazole,4,5,6-(5,6,7)-tribromo-1- (tripropionyl D ribofuranosyl)-benzimidazo1e,4,5,6- (5,6,7) trichloro 1 (tributyryl-D-ribofuranosyD-benzimidazole and4,5,6-(5,6,7)-tribromo-l-(tribeuzoyl-D-ribofuranosyD-benzimidazole.

Other halogenated compounds may also be employed in place of the1-chloromercuri-4,5,6-(5,6,7) trichlorobenzimidazole. For example,compounds such as l-bromomercuri-4,5,6- 5,6,7) -tribromobenzimidazole,l-chloromercuri 4,S-dichloro-G-bromo-(6,7-dichloro-5-bromo)-benzimidazole, 1 chloromercuri-4,5-dibromo-6-chloro- (6,7dibromo-S-chloro)-benzimidazole, l-chloromercuri-4,6-dichloro-5-bromo-(5,7-dichloro-6-bromo) beuzimidazole, lchloromercuri-4,5,6-(5,6,7) tri-iodo-benzimidazole,"1-chlommercuri-4,S-dichloro-G-iodo-(6,7-dichloro-5- iodo)-benzimidazolemay be reacted with 1-halo-2,3,5- triacyl-D-ribofuranose to form4,5,6-(5,6,7)-tribromo-l- (triacyl Dribofuranosyl)-benzimidazole,4,5-dichloro-6- bromo(6,7-dichloro-5-bromo)-1-(triacyl-D-ribofuranosyl)-benzimidazole',4,5-dibromo-6-chloro-(6,7-dibromo-5- chloro)l-(triacyl-D-ribofuranosyl)-benzimidazole, 4,6- dichloroS-bromo-(5,7-dichloro-6-bromo)-1-(triacyl-D- ribofuranosyl)benzimidazole, 4,5,6-(5,6,7)-tri-iodo-1- (triacylD-ribofuranosyl)-benzimidazole, and 4,5-dichloro 6iodo-(6,7-dich1oro-5-iodo)-l-(triacyl-D-ribofuranosyl)-benzimidazole.

PREPARATION OF 4,5,6-(5,6,7)-TRICHLORo-1-D- 'RIBOFUBANOSYLBENZIMIDAZOLEMethanol (250 ml.) was saturated with anhydrous ammonia at C. (about 70g. required). To this solution was added 7.0 g. of4,5,6-(5,6,7)-trichloro-l-(triacetyl- D-ribofuranosyl)-benzimidazole in100 ml. of methanol. The solution was placed in the cold room for about16 hours. It was then concentrated under reduced pressure giving analmost completely crystalline solid. This was dissolved in 110 ml. ofhot 50% ethanol, treated with activated-charcoal and filtered by gravitywith two ml. solvent rinses. Itwas cooled to room temperature, seededand allowed to crystallize at room temperature with frequent stirringand then refrigerated overnight. The crystals were collected and washedwith a small quantity of cold 50% ethanol. After drying in vacuo overpotassium hydroxide the product weighed 2.25 g., M. P.215-217" C.(softening at 210 C.). This product was dissolved in 70 m1. of hot 50%ethanol, treated with activated charcoal and filtered by gravity withtwo 2.5 ml. solvent rinses. It was allowed to crystallize at roomtemperature and then refrigerated. The colorless crystals werecollected, washed with cold 50% ethanol and dried in vacuo overpotassium hydroxide. The product, 4,5,6-(5,6,7)-trichloro-1-Dribofuranosylbenzimidazole, weighed 1.82 g., M. P. 230-232 C.

An analytical sample wasprepared as follows: One gram was dissolved in100 m1. of methanol and filtered by gravity with a 10 ml. methanolrinse. Then 850 ml. of isopropyl ether (dried over anhydrous magnesiumsulfate) was added. Precipitation was very slow at room temperature, butincreased somewhat when the solution was seeded and scratched. Afterovernight refrigeration, the colorless precipitate was collected andWashed with methanol-isopropyl ether mixture (1:10 by volume) and thenwith petroleum ether (B. P. 3060). Dried in vacuo over potassiumhydroxide, the 4,5,6-(5,6,7)-trichloro-1-D-ribofuranosylbcnzimidazoleweighed 0.51 g., M. P.216-218 C. The sample was dried two hours at 100C. in vacuo over phosphorous pentoxide.

Analysis-Calculated for C12H1104N2Cl3: C, H; 3.14; N, 7.92. Found: C,41.00; H, 3.39; N, 8.42.

A second run starting with 20.52 g. (0.045 mole) of I1-chloromercuri-4,5,6-trichlorobenzimidazole. and 14.33

8 g; (0.045 mole) of tetracetyl-D ribofuranose gave 14.1 g. of4,5,6-(5,6,7)-trichloro-1-(triacetyl D ribofuranosyl)-benzimidazole.Deacetylation followed by two crystallizations from ethanol gave 3.85g., M. P. 230231 C., of 4,5,6-(5,6,7)-trichloro-1-D-ribofuranosylbenzimidazole.

Analysis.Calculated for C H O N Cl C, 40.76; H, 3.14; N, 7.92. Found: C,40.79; H, 2.84; N, 8.19.

In like manner other 4,5,6-(5,6,7)-trihalo-l-(triacyl-D-ribofuranosyl)-benzimidazole compounds may be hydrolyzed. For example4,5,6-(5,6,7)-tribromo-1-triacyl- D-ribofuranosyl)-benzimidazole,4,5-dichloro-6-bromo- (6,7 dichloro 5 bromo) 1 (triacyl D ribofuranosyl)-benzimidazole, 4,5-dibromo-6-chloro- 6,7-dibromo-5- chloro) 1 (triacylD ribofuranosyl) benzimidazole, 4,6 dichloro 5 bromo (5,7 dichloro 6bromo) ltriacyl-D-ribofuranosyl -benzimidazole, 4,5 ,6 (5,6,7tri-iodo-l-(triacyl-D-ribofuranosyl)-benzimidazole or 4,5- dichloro 6iodo (6,7 dichloro 5 iodo) 1 (triacyl-D-ribofura'nosyl)-benzimidazolemay be hydrolyzed to form4,5,6-(5,6,7)-tribrorno-1-D-ribofuranosyl-benzimidazole,4,5-dichloro-6-bromo-(6,7-dichloro-5 brorno)-1-D-ribofuranosylbenzimidazole, 4,5-dibromo-6-chloro (6,7 dibromo 5chloro) l D ribofuranosylbenzimidazole, 4,6 dichloro 5 bromo (5,7dichloro 6 bromo) 1 D ribofuranosylbenzimidazole, 4,5,6 (5,6,7) tri iodo1 D ribofuranosylbenzimidazole and'4,5-dichloro-6-iodo-(6,7-dichloro-5-iodo)-1-D-ribofuranosylbenzimidazole.

PREPARATION OF 4,5,6-(5,6,7)-TRIGHLORO-1D-RIBO- vFURANOSYLBENZIMIDAZOLILHYDROCHLORIDE 4,5,6 (5,6,7) trichloro- 1 D ribofuranosylbenzi-'rnidazole hydrochloride may be prepared by dissolving 4,5,6 (5,6,7)trichloro 1 D ribofuranosylbenzimidazole in dry ethanol, saturating thesolution with dry hydrogen chloride and adding ether to precipitate4,5,6- (5,6,7)-trichloro-l-D-ribofuranosylbenzirnidazole hydrochloride.

Example 2 PREPARATION OF 4,5,6-TRIBROMOBENZIMIDAZOLE A mixture of 7 g.of crude 1,2,3-tribromo-4,5-diamino benzene, ml. of formic acid, 50 ml.of hydrochloric acid and ml. of water was refluxed for live hours. Thereaction mixture was diluted with water, heated to boiling and activatedcharcoal was added. After filtering and cooling, the solution was madealkaline with ammonium hydroxide, whereupon a precipitate formed. Theprecipitate was collected, washed with Water and dried. The precipitatewas recrystallized from 3 liters of benzene to yield 19 g. of4,5,6-tribromobenzimidazole which had a melting point of 231-234 C.

Analysis.Calculated for C H N Br C, 23.69; H,

, 0.85; N, 7.90. Found: C, 23.62; H, 0.81; N, 8.15.

PREPARATION OF 1-CHLOROMERCURI-4,5,6-(5,6,7)-

TRIBROMOBENZIMIDAZOLE To a solution of 14.2 g. of4,5,6-tribromobenzimidazole in-165 ml. of 50% ethanol was added 44 ml.of 1 N sodium hydroxide. While the solution was heated and stirred, amixture of 10.9 g. of mercuric chloride in ml. of hot ethanol was added.The gelatinous precipitate became grainy after about one hour of heatingand stirring. The 1-chloromercuri-4,5,6-(5,6,7)-tribromobenzimidazolewas collected, washed with water and dried.

PREPARATION OF 4,5,6-(5,6,7)-TRIBROMO-1-(TRI-ACETYL-D-RIBOFURANOSYL-BENZIMIDAZOLE1-chloro-2,3,S-triacetyl-D-ribofuranose was prepared by dissolving 9.87g. of tetraacetyl-D-ribofuranose which had been ground and dried overphosphoric anhydride, in 200 ml. of dry ether. The solution wassaturated with anhydrous hydrogen chloride at 0 C. and stored at 4 C.for 4 days. The solution was concentrated under reduced pressure to asirup. Threeportions of dry benzene were collected and washed withpetroleum ether. The precipi-.

tate was extracted with four 100 ml. portions of hot chloroform. Thechloroform extracts were combined and washed with two 150 ml. portionsof 30% potassium iodide, then twice with water. The chloroform layer,after drying over anhydrous magnesium sulfate was concentrated underreduced pressure. Most of the residue 4,5,6 (5,6,7) tribromo l(triacetyl D ribofuranosyl)-benzirnidazole crystallized from solution.

PREPARATION OF 4,5,s- 5,6,7 mnrBnoMod-o-nnso FURANOSYLBENZIMIDAZOLE The4,5,6-(5,6,7)-tribromo-1-(triacetyl-D-ribofuranosyl)-benzimidazole thusobtained was dissolved in 800 ml. of methanol. The solution wassaturated with ammonia at C. and maintained at 4 C. for about sixteenhours. The methanol solution was concentrated under reduced pressure.The crystals that formed were collected and recrystallized from hotmethanol to form 3.6 g. of 4,5,6-

(5,6,7)-tribromo-1-D-ribofuranosylbenzimidazole having a melting pointof 230-235 C. pyridine).

Analysis.-Calculated for C H N O Br C, 29.59; H, 2.28; N, 5.75. Found:C, 30.10; H, 2.67; N, 5.97.

Example 3 PREPARATION OF 1-BROMO-2,G-DICHLORO-l-NITRO- BENZENE Thirtyone g. (0.15 mole) of a 2,6-dichloro-4-nitroaniline was practically alldissolved in 200 ml. of sulfuric acid (sp. gr. 1.84). The solution wasstirred and cooled in an ice-salt bath to about 0 C. A solution of 10grams of sodium nitrite in 100 ml. of sulfuric acid (sp. gr. 1.84) wasadded over a period of about 5 minutes. While the solution was stirredand maintained at 0 C. to 5 C., 200 ml. of 85% phosphoric acid was addedover a period of 45 minutes. The stirring was continued at about 5 C.for another 1.5 hours.

Cuprous bromide, prepared from 63 g. of cupric sulfate, 28.5 g. ofsodium bromide and 16 g. of sodium sulfite was dissolved in 200 ml. ofhydrobromic acid (sp. gr. 1.49). This solution was stirred vigorouslywhile the diazonium solution was added under the surface as rapidly asthe foaming due to the evolution of nitrogen would permit. The darkmixture which resulted was heated on a steam bath for 40 minutes. Aftercooling, it was poured over ice. The yellow solid1-bromo-2,6-dichloro-4-nitrobenzene separated and was collected andwashed with water.

The yellow solid was dissolved in hot benzene, the solution was driedover anhydrous magnesium sulfate, filtered and concentrated to dryness.The residue was dissolved in hot ethanol. 0n cooling, light yellowcrystals separated. After recrystallization from ethanol the meltingpoint of the l-bromo-2,6-dichloro-4-nitrobenzene was 8890 C.

PREPARATION OF 1-BROMO-2,6-DICHLOR04,5-DINTRO- BENZENE 17.3 g. (0.064mole) of 1-bromo-2,6-dichloro-4-nitrobenzene was dissolved in 75 m1. offuming nitric acid and 75 ml. of sulfuric acid (sp. gr. 1.84). Twolayers formed. The mixture was heated on a steam bath for two hours withfrequent shaking. After cooling, the

10 reaction mixture was poured over ice. The yellow solid which formedwas crystallized from 50% ethanol to yield 18.9 g. (94%)1-brom0-2,6-dichloro-4,5-dinitrobenzene having a melting point of126-130 C.

PREPARATION OF 1-BROMO-2,6-DICHLORO-=l,5- DIAMINOBENZENE To a suspensionof 18.9 g. (0.06 mole) of l-bromo-2,6- dichloro-4,5-dinitrobenzene inml. of hydrochloric acid (sp. gr. 1.19) was added 24 g. of mossy tin inpieces as the mixture was heated on a steam bath and frequently shaken.After the reaction was completed, water was added to the mixture to makeabout 1 liter and the mixture was boiled to dissolve the product.Activated charcoal was added to the reaction mixture and the mixture wasfiltered. The filtrate was made strongly alkaline with sodium hydroxide.The precipitate 1-bromo-2,6-dichloro- 4,5-diaminobenzene which formedwas collected and dried. The solid material was extracted with ether.The ether extract was concentrated to dryness to yield 14.3 g. (93%) ofcrude 1-bromo-2,6-dichloro-4,5-diaminobenzene.

PREPARATION OF 5 (6)-BROMO- l,6- (5,7 DICHLORO- BENZIMIDAZOLE To 14.3 g.of l-bromo-2,6-dichloro-4,5-diaminobenzene was added 75 ml. of formicacid and 240 ml. of 4 N hydrochloric acid. The mixture was refluxed for3 hours and boiling water was added to the mixture until the productdissolved. Activated charcoal was added to the solution and the mixturefiltered. The 5-bromo-4,6- dichlorobenzimidazole hydrochloridecrystallized when the solution was cooled. The cooled mixture was madealkaline with ammonium hydroxide. The precipitate was collected, washedwith water and dried.' After two recrystallizations from benzene, 9 g.(61%) of 5(6)- bromo 4,6(5,7) dichlorobenzimidazole, melting point224226 C., was obtained.

Analysis.-Calculated for C H BrCl N C, 31.61; H, 1.14. Found: C, 31.88;H, 1.18.

PREPARATI ON OF l-CHLOROMERCURI-5 6 -BROMO- 4,6- (5,7)-DICHLOROBENZIMIDAZOLE Nine grams of 5(6)-bromo-4,6(5,7)-dichlorobenzimidazole was dissolved in ml. of hot 50%ethanol and 35 ml. of 1 N sodium hydoxide was added. While the solutionwas stirred and heated on a steam bath, 9.2 g. of mercuric chloridedissolved in 100 ml. of hot ethanol was added. After 40 minutes ofheating and stirring, the precipitate, l-chloromercuri-S (6 -bromo-4,6(5,7) dichlorobenzimidazole, became granular. It was collected andwashed with hot water, and weighed 16.6 g. (98%).

PREPARATION OF 5(6)BROMO4,6-(5,7)-DICHLORO-l-(TRIACETYL-D-RIBOFURANOSYL)-BENZIMIDAZOLE A suspension of 16.6 g. ofl-chloromercuri-5(6)-bromo- 4,6-(5,7)-dichlorobenzimidazole in 1100 ml.of dry xylene was prepared. About 100 ml. of xylene was distilled off toremove any water in the mixture. l-chloro-2,3,5triacetyl-D-ribofuranose, prepared by suspending 9.87 g. of1,2,3,5-tetraacetyl-D-ribofuranose in 50 m1. of dry xylene was added tothe hot suspension. The mixture was refluxed with stirring for 4 hours.After cooling, 3 liters of petroleum ether was added and the precipitatewas collected and Washed with petroleum ether. After drying, theprecipitate was extracted with four 100 ml. portions of hot chloroform.The chloroform extracts were washed with two 150 ml. portions of 30%potassium iodide followed by two portions of water. After drying overanhydrous magnesium sulfate, the chloroform solution was concentrated toa yellow oil containing crude 5(6)- bromo 4,6 (5,7) dichloro 1(triacetyl D ribofuranosyl)-benzimidazole.

PREPARATION OF 5 (6 -BROMO-4,6- (5,7 -DICHLORO-1- I The crude 5 (6-bromo-4,6- 5,7 -dichlorol-(triacetyl- D-ribofuranosyl)-benzimidazole in120 ml. of methanol was added to 250 ml. of methanol which had beensaturated with ammonia at C. The solution was stored at 4 C. overnight.The resulting solution was concentrated to an oil which was dissolved inabout 130 ml. of hot 50% ethanol. After cooling, 1.62 g. of crystals of(6) bromo 4,6 (5,7) dichloro l ([i-D-ribofuranosyl) benzimidazole werecollected and washed with 50% ethanol, melting point 203-217 C. Thefiltrate was concentrated until crystals began to form. This crop ofcrystals had a melting point of 171-204 C.

, The first crop was recrystallized several times from methanol to give5(6)-bromo-4,6(5,7)-dichloro-l-(flribofuranosyl)-benzimidazole, meltingpoint 217-219 C., [a] 61:2 (C. 1,pyridine).

Analysis-Calculated for C H BrCl N O C, 36.21; H, 2.79; N, 7.04. Found:C, 36.07; H, 3.03; N, 7.17.

When the second group was crystallized from methanol, two types ofcrystals formed: small granules that grew on the glass and clumps ofprisms. Mechanical separation of the clumps of prisms followed byseveral recrystallizations from methanol resulted in a small amount of5(6) bromo 4,6 (5,7) dichloro 1 (oz D ribofur anosyl)-benzimidazole,melting point 193-196 C.,

Analysis.-Found: C, 36.78; H, 3.28; N, 7.54.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of this invention.

We claim:

1. 1-halomercuri-4,5,6-(5,6,7 -trihalobenzimidazole.

30 Beilstein: (Handbuch der 12 2. l chloromercuri- 4,5,6-( 5,6,7)trichlorobenzimidazole.

, 3. 1 chloromercuri 4,5,6-(5,6,7) tribromobenzimidazole.

5 '4. l chloromercuri 5(6) bromo 4,6 (5,7) di- 6. The process whichcomprises reacting 4,5,6 trich1orobenzimidazole with mercuric chlorideto form l-chloromercuri-4,5,6-trichlorobenzimidazole.

7. The process which comprises reacting 4,5,6-tribromo- 'benzimidazolewith mercuric chloride to form l-chloro- 15mercuri-4,5,6-tribromobenzimidazole.

8. The process which comprises reacting 5 (6)-bromo- 4,6(5,7)-dichlorobenzimidazole with mercuric chloride to forml-chloromercuri-S(6)-bromo-4,6-(5,7)-dichlorobenzimidazole.

References Cited in the file of this patent UNITED STATES PATENTS OTHERREFERENCES Tamm: Science, vol. 120, pages 847-8 (1954). i Tamm: Chem.Abstracts 120, vol. 49, column 16066; f (l955). Org. Chem, 4th ed.),vol. 23, pages 134-135 (1936).

Elderfield: Heterocyclic Compounds, vol 5, pp. 274-

1. 1-HALOMERCURI-4,5,6-(5,6,7)-TRIHALOBENZIMIDAZOLE.